Persistent postsurgical pain: evidence from breast cancer surgery, groin hernia repair, and lung cancer surgery.

Persistent Postsurgical Pain: Evidence from Breast Cancer Surgery, Groin Hernia Repair, and Lung Cancer Surgery Mads Utke Werner and Joakim Mutahi Bischoff

Abstract The prevalences of severe persistent postsurgical pain (PPP) following breast cancer surgery (BCS), groin hernia repair (GHR), and lung cancer surgery (LCS) are 13, 2, and 4–12 %, respectively. Estimates indicate that 80,000 patients each year in the U.S.A. are affected by severe pain and debilitating impairment in the aftermath of BCS, GHR, and LCS. Data across the three surgical procedures indicate a 35–65 % decrease in prevalence of PPP at 4–6 years follow-up. However, this is outweighed by late-onset PPP, which appears following a pain-free interval. The consequences of PPP include severe impairments of physical, psychological, and socioeconomic aspects of life. The pathophysiology underlying PPP consists of a continuing inflammatory response, a neuropathic component, and/or a late reinstatement of postsurgical inflammatory pain. While the sensory profiles of PPP-patients and pain-free controls are comparable with hypofunction on the surgical side, this seems to be accentuated in PPP-patients. In BCS-patients and GHR-patients, the sensory profiles indicate inflammatory and neuropathic components with contribution of central sensitization. A number of surgical factors including increased duration of surgery, repeat surgery, more invasive surgical techniques, and intraoperative nerve lesion have been associated with PPP. One of the most consistent predictive factors for PPP is high intensity acute postsurgical pain, but also psychological factors including anxiety, catastrophizing trait, depression, and psychological vulnerability have been identified as significant predictors of PPP. The quest to identify improved surgical and anesthesiological techniques to prevent severe pain and functional impairment in patients after surgery continues.

M. U. Werner (&) J. M. Bischoff Multidisciplinary Pain Center 7612, Neuroscience Center, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark e-mail: [email protected] J. M. Bischoff e-mail: [email protected]

Curr Topics Behav Neurosci DOI: 10.1007/7854_2014_285 Springer-Verlag Berlin Heidelberg 2014

M. U. Werner and J. M. Bischoff

Keywords Breast cancer surgery Chronic pain cancer surgery Outcome Postoperative pain

Groin hernia repair Lung

Contents 1 2

Introduction.............................................................................................................................. When is Pain Persistent?......................................................................................................... 2.1 Definitions....................................................................................................................... 2.2 Duration of Persistent Pain ............................................................................................ 3 Demographics .......................................................................................................................... 4 Behavioral Impairment............................................................................................................ 4.1 General Issues in Chronic Pain (Non-cancer) ............................................................... 4.2 Persistent Pain After Breast Cancer Surgery................................................................. 4.3 Persistent Pain After Groin Hernia Repair .................................................................... 4.4 Persistent Pain After Lung Cancer Surgery .................................................................. 5 Pathophysiology....................................................................................................................... 5.1 General Aspects .............................................................................................................. 5.2 Quantitative Sensory Testing ......................................................................................... 6 Predictive Factors .................................................................................................................... 6.1 Surgical Factors .............................................................................................................. 6.2 Psychological Factors ..................................................................................................... 6.3 Socioeconomic Factors ................................................................................................... 6.4 Biological Factors ........................................................................................................... 7 Future Research Strategies...................................................................................................... 8 Conclusion ............................................................................................................................... References......................................................................................................................................

1 Introduction Persistent pain after surgical procedures remains a major surgical and medical problem (Kehlet et al. 2006; Kehlet and Rathmell 2010; Dworkin et al. 2010; Rappaport et al. 2010; Buvanendran 2012). The estimated annual surgical volumes in the U.S.A. of breast cancer surgery (BCS), groin hernia repair (GHR) and lung cancer surgery (LCS) are 480,000, 600,000, and 80,000, respectively.1 Since 2–10 % of these patients will develop severe persistent postsurgical pain (PPP) (Kehlet et al. 2006), this is a huge and daunting problem for the individual and the community. GHR, a seemingly minor surgical procedure with superficial, limited tissue injury, illustrates the problem. The patient has felt a lump in the groin area and has 1

Extrapolated from http://www.cancer.gov/cancertopics/types/breast, http://www.sages.org/ publication/id/PI06/, http://www.cancer.gov/cancertopics/types/lung, studies (Wildgaard et al. 2011; Walters et al. 2013) and a review (Kehlet et al. 2006).

Persistent Post-Surgical Pain Table 1 Prevalence of persisting postsurgical pain in BCS, GHR, and LCS Surgical procedure

Author

Year Number Method

Breast cancer surgery

Mejdahl et al. (2013) Andersen et al. (2011) Gärtner et al. (2009) Vilholm et al. (2008) Bright et al. (2010) Loos et al. (2007) Haapaniemi et al. (2002) Bay-Nielsen et al. (2001) Wildgaard et al. (2011) Wildgaard et al. (2009) Keller et al. (1994) Kalso et al. (1992)

2013

Groin hernia repair

Lung cancer surgery

Pain intensity

2,411

Questionnaire Moderate to severe 2011 15,697 Review Moderate to severe 2009 3,754 Questionnaire Moderate to severe 2008 258 Questionnaire Moderate to severe 2010 9,607 Questionnaire Severe 2007 2002

1,766 264

2001

1,169

2011

546

2009

2,586

1994

238

1992

150

Questionnaire Severe Questionnaire Moderate to severe Questionnaire Moderate to severe Questionnaire Moderate to severe Review Moderate to severe Questionnaire Moderate to severe Questionnaire Moderate to severe

Pain prevalence (%) 16 25–60 52 24 1–3 2 5 3–8 11–18 3–16 11 44

experienced regional discomfort. The general practitioner tells the patient of the necessity of surgery, due to the risk of development of irreducibility of the hernia, a condition which may lead to strangulation of an intestinal loop and subsequent life-threatening septicemia. The patient accepts this and is admitted for open surgery. After uncomplicated anesthesia and surgery, the patient wakes up quite unprepared for a nightmare of persisting pain and disability. About 1–3 % of postsurgical hernia patients (e.g. 6,000-18,0002 patients each year in the U.S.A.) are affected by severe persisting and disabling inguinal post-herniotomy pain that may lead to functional and socioeconomic disability (Bay-Nielsen et al. 2001; Loos et al. 2007). In other surgical procedures, e.g., BCS, involving larger tissue volumes and including deeper structures, and when adjuvant chemotherapy or radiotherapy is added, the risk of developing persistent pain increases fivefold or more, as compared to GHR (Table 1). In this chapter, the aftermath of three surgical procedures is studied: BCS, GHR, and LCS. These procedures are quite different in regard to patient population (age, gender, concomitant diseases), surgical techniques and composition of tissues 2

http://www.sages.org/publication/id/PI06/


in the surgical field (nerve density), and adjuvant treatments (chemotherapy, radiotherapy). Also, each procedure presents with specific patterns of postoperative morbidities, including pain and functional impairment.

2 When is Pain Persistent? 2.1 Definitions The prevalent definition of PPP presented in the literature, is pain in or near the surgical area, continuing beyond 3–6 months after surgery, without signs of a postsurgical complication (Kehlet et al. 2010; Macrae 2008). Attempts to use a more operative definition of chronic pain, i.e., pain that does not have a biological meaning and continues for more than 3–6 months (Cousins 2007), may seem to fail in PPP since low-grade chronic inflammation in the tissues, around foreign bodies (implants), may contribute to pain for prolonged periods of time. Based on the current definition (Kehlet et al. 2010; Macrae 2008), updated criteria for PPP are presented in Table 2 (Werner and Kongsgaard 2014). These criteria indicate that PPP may occur after a pain-free period; that is, development of PPP cannot automatically be considered to follow a direct trajectory from acute to chronic pain. In BCS and GHR, late-onset PPP has been demonstrated (Reinpold et al. 2011; Mejdahl et al. 2013). Some tentative reasons for this bi-phasic (acute-chronic) response are: first, nerve damage sometimes is associated with a delayed onset of neuropathic pain symptoms. Indeed, neuropathic pain components are considered a major contributor to PPP (Kehlet et al. 2006; Borsook et al. 2013). Second, in implant surgery, partial dehiscence of the inguinal mesh or dislocation of orthopedic prosthetic material may lead to PPP after a painfree postsurgical period. Some authors, however, do not consider this PPP, but rather to reflect a mechanical complication following surgery (Kehlet et al. 2012). Third, reinstatement of pain-like behavior has been observed in experiments following a deep tissue injury. Several weeks after complete recovery from pain-like behavior in mice, administration of naltrexone, a l-opioid receptor antagonist, leads to reinstatement of tactile hypersensitivity, guarding behavior, and pain behavior (Campillo et al. 2011; Corder et al. 2013). During the resolution of the injury, endogenous receptor activity enhances pain inhibitory signaling. This up-regulated, tonic activation of endogenous opioid receptors, blocked by naltrexone, seems responsible for the attenuation of latent sensitization, persisting beyond the resolution of the injury. Administration of the l-opioid receptor antagonist leads to blockade of the endogenous opioid system and uncovering of latent sensitization. Translational research in humans has not yet uncovered an analogous mechanism in man (Pereira et al. 2013), although recent data seem to indicate that use of very high doses of naloxone at least in some volunteers may lead to uncovering of latent sensitization (unpublished observations, MUW).

Persistent Post-Surgical Pain Table 2 Proposed criteria for PPP (Werner and Kongsgaard 2014) 1. The pain develops after a surgical procedure or increases in intensity after the surgical procedure 2. The pain should be of at least 3– 6 months’ duration and significantly affect the HR-QOL 3. The pain is either a continuation of acute post-surgery pain or develops after an asymptomatic period 4. The pain is either localized to the surgical field, projected to the innervation territory of a nerve situated in the surgical field, or referred to a dermatome (following surgery in deep somatic or visceral tissues) 5. Other causes of the pain should be excluded, e.g., infection or continuing malignancy in cancer surgery

2.2 Duration of Persistent Pain What is the trajectory of ‘‘classical’’ PPP, i.e., acute pain progressing directly into chronic pain? A study examining the sequential prevalence of PPP after GHR (n = 736) demonstrated that 65 % of the patients with PPP 6 months after surgery were pain free at the 5-year follow-up (Reinpold et al. 2011). The prevalence of PPP in 600 patients examined at intervals after lung surgery was 57 % at 7–12 months, 36 % at 4–5 years, and 21 % at 6–7 years (Maguire et al. 2006). However, it should be noted that only 40 % of the patients in this study had surgery performed due to malignancy. The data from BCS-, GHR-, and LCSpatients thus indicate a decrease, of considerable magnitude, in prevalence of patients with PPP at 5–6 years follow-up, compared with the prevalence at 6 months. Surprisingly, while the pain prevalence decreased with time, pain severity did not seem to lessen with time (Maguire et al. 2006). Evidence for lateonset of PPP is discussed below (Sect. 4.3).

3 Demographics A number of scientific papers deserve particular recognition for highlighting the challenge of PPP (Kehlet et al. 2006; Macrae and Davies 1999; Perkins and Kehlet 2000). The authors of these papers unanimously called for improved research in what they perceived was an unrecognized and therefore undertreated area (Kehlet and Rathmell 2010; Kehlet et al. 2010; Macrae 2008). The papers clearly illustrated that PPP is a major problem compromising various physical, psychological, and socioeconomic aspects of life in 10–60 % of postsurgical patients, depending not only on surgical procedures and surgical techniques, but also on patient-related and pain management-related factors. In BCS, GHR, and LCS a large number of questionnaire studies on the prevalence of PPP have been published (Table 1). Though the prevalence of severe PPP depends on pain intensity criteria, resting or dynamic assessment conditions,


and the time elapsed after the surgical procedure (Mejdahl et al. 2013), the reported prevalences of severe persistent pain in BCS, GHS, and LCS are in the order of 13 % (Gartner et al. 2009), 2 % (Loos et al. 2007), and 4–12 % (Wildgaard et al. 2011), respectively. Recently published data from a 6-year follow-up on BCS-patients indicate that ‘‘the problem is not static as it can either progress or regress with time’’ (Mejdahl et al. 2013).

4 Behavioral Impairment 4.1 General Issues in Chronic Pain (Non-cancer) Physical impairment due to chronic pain may lead to a number of restrictions in everyday life. Several studies (Breivik et al. 2006; O’Brien and Breivik 2012) and reviews (Reid et al. 2011) have demonstrated a range of impaired activities of daily living (ADL) present in chronic pain patients; from cleaning, dressing, shopping, stair climbing, vacuum cleaning, walking, and maintaining social relations to engaging in sexual activity. These physical restrictions are also mirrored in psychological changes which are more prevalent in chronic pain patients than in the population; anxiety; catastrophizing traits; cognitive disturbances; depression; psychological vulnerability; and somatization traits (Fishbain 2013). A recent study investigated the correlation between self-reported severe pain and socioeconomic issues (Morgan et al. 2011), i.e., ‘‘social deprivation,’’ employment status and social security. Pain status was recorded for a population cohort consisting of more than 9,400 subjects; 62 % reported no pain, 33 % reported moderate pain while nearly 5 % reported severe chronic pain. The group with severe pain had significantly higher odds ratios of belonging to the lowest income group, of living in areas with overrepresentation of multiple social deprivation, compared to more affluent areas, and, of belonging to United Kingdom’s National Statistics Socio-economic Classification Class 7 (routine occupations) and Class 8 (never worked/long-term unemployed). In individuals of working age with severe chronic pain, almost 45 % stated they were unable to work due to sickness or disability and 40 % claimed a state benefit, related to the disability. These socioeconomic data are corroborated in several reviews (Reid et al. 2011; Patel et al. 2012; Moore et al. 2014) and large scale studies (Langley et al. 2010a, b; Becker et al. 1997, 2000; Currow et al. 2010). Not unexpectedly, ratings of health-related quality of life (HR-QOL) issues are associated with markedly lower scores in pain patients than in the population as a whole (Moore et al. 2014). The life expectancy for chronic pain patients also seems lower than for controls, with relative risk ratios for premature death of 1.1–2.4 (Moore et al. 2014). Decreased physical activity, depression, and disrupted sleep architecture are contributing factors to the principal causes of death: cardiovascular and respiratory failure.

Persistent Post-Surgical Pain

Quite a number of assessments scales of psychological and physical function impairment are used in research on chronic pain. Some of the validated general assessment scales, applicable in a number of pain conditions, are Short Form Health Survey (SF-36) (Ware and Sherbourne 1992), the Brief Pain Inventory (BPI) (Cleeland 1991), the Pain Disability Index (PDI) (Tait et al. 1987) and the Multidimensional Pain Inventory (MPI) (Kerns et al. 1985). Disease-specific assessments scales are the Western Ontario and McMaster Universities Arthritis Index (WOMAC) (Bellamy et al. 1988). Functional Assessment of Cancer Therapy General Questionnaire (FACT-G3) (Cella et al. 1993; Webster et al. 2003) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ) (Aaronson et al. 1993). The commonly used Short Form Health Survey (SF-36) questionnaire assesses several distinct domains: physical functioning, physical and emotional impediments to role functioning, pain, general health, vitality (fatigue, energy), social functioning, and mental health (Parker et al. 2007), comparable in construction to the EORTC-QLQ-C30.

4.2 Persistent Pain After Breast Cancer Surgery In BCS, impairments in postsurgical HR-QOL and ADL issues are related to the surgical procedure, depending on several factors: magnitude of breast tissue injury [breast conserving surgery (lumpectomy, quadrantectomy), mastectomy]; invasiveness [sentinel lymph node resection (SLNR),4 axillary lymph node resection]; adjuvant treatment (chemotherapy, hormonal therapy, immunotherapy, radiotherapy); and cancer stage (Rietman et al. 2003, 2006; Vilholm et al. 2009). The EORTC-QLQ-C30 supplemented by the specific breast module EORTCQLQ-BR23 has been used in more than 40 % of studies examining HR-QOL-issues in BCS-patients (Lemieux et al. 2011). These questionnaires evaluate cognitive, emotional, physical, sexual and social functioning, body image, distressing symptoms (fatigue, nausea), side-effects of treatment, and socioeconomic difficulties. The breast cancer-specific FACT-G [including the breast cancer module (FACT-B)]) has been used in 25 % of the studies. The SF-36 has been used in more than 10 % of BCS studies concerned with QoL-assessments (Lemieux et al. 2011; Chopra and Kamal 2012), but is not cancer-specific. The relationship between HR-QOL evaluations and ADL assessments are statistically significant (Rietman et al. 2003). Low HR-QOL scores are associated with impairment of daily activities. 3

Related to FACIT-G = Functional Assessment of Chronic Illness Therapy General Questionnaire 4 Sentinel lymph node assessment is a minimal invasive technique for detection of regional metastases. Sentinel lympnodes are identified by preoperative administration near the cancer of a radioactive isotope (Tc-99 m), followed by intraoperative tracing by a simple dye. Following excision of the sentinel lymp nodes intraoperative histological analyses are made. If signs of regional spread exist axillary lymph node excision is performed.


Reciprocally, however, the strength of the interdependence is affected by patientrelated factors, domains examined, and context factors. Congruent findings have been observed in the relationship between HR-QOL and ADL, and pain (Rietman et al. 2003; Tasmuth et al. 1996). The number of publications registered in PubMed on HR-QOL and ADL issues in BCS-patients, exceed more than 1,000, demonstrating the scientific interest and importance of this field. The hitherto largest bibliographical review on HR-QOL in breast cancer patients includes 477 studies (n = 85,000) (Montazeri 2008), published from 1974 to 2007. Obviously, the study covers a span of three decades and contains significant time-related changes in diagnosis, technology, and treatment procedures—necessitating cautious interpretation of data. However, the review concludes, first, that patients undergoing mastectomy compared to breast conserving surgery usually reported a more negative body image perception. Second, almost all studies indicated that BCS-patients receiving chemotherapy and adjuvant hormonal therapies experienced side-effects that negatively affected the HR-QOL. Persistent fatigue, pain, postmenopausal symptoms, psychological distress, i.e., anxiety and depression and upper limb morbidity, were among the most common symptoms reported. Third, sexual functioning was impaired, particularly in younger patients, thus negatively affecting HR-QOL. These findings are probably best illustrated in a study from 2006 in breast cancer patients (n = 180), where upper limb morbidity [arm volume, muscle strength, range of motion (shoulder disability)], ADL disability, and HR-QOL were examined (Rietman et al. 2006). Treatment-related upper limb morbidity, associated ADL disabilities, and decreased HR-QOL were documented 2 years after surgery, and compared to the presurgery level. The patients receiving axillary lymph node dissection (ALND, 70 %) experienced significantly more upper limb morbidity, ADL disabilities and decreased HR-QOL, than patients receiving SLNR. These data have recently been corroborated in a 7-year follow-up after surgery in the same cohort (Kootstra et al. 2013). Sensory disturbances or discomfort, potentially affecting everyday life, occurs in 60 % of BCS-patients, depending on the surgical and adjuvant treatment (Gartner et al. 2009). In patients undergoing SLNR and radiotherapy to the residual breast tissue, the prevalence of sensory disturbances or discomfort was 30 %, while in patients also receiving ALND and chemotherapy or loco-regional radiotherapy, the prevalence increased to 85 %. Most frequently reported locations were the axilla (65 %), arm (50 %), breast area (45 %), and the lateral side of the body (30 %).

4.3 Persistent Pain After Groin Hernia Repair The sex ratio (females/males) of GHR is 1/9, and data indicate a significantly higher prevalence of PPP in females compared to males, 23 and 11 %, respectively (Kalliomaki et al. 2008). An early nationwide questionnaire study in 1,170


individuals 1 year after open (98 %) GHR, demonstrated that 17 % experienced physical limitations during work, sport, or other leisure activities, likely as a consequence of chronic groin pain (Bay-Nielsen et al. 2001). In addition, 20–32 % experienced pain from the groin when standing up more than 30 min, climbing stairs, sitting more than 30 min, and getting up from a chair. These restrictions in physical functioning are in agreement with the results of several other GHRstudies (Poobalan et al. 2001; Mikkelsen et al. 2004; Grant et al. 2004). In a follow-up study, 6 years after the GHR in the same patients, 75 % had less pain, while only 25 % had the same pain intensity level or higher (Aasvang et al. 2006a). The GHR-related impact on ADL functions decreased from 17 % at the 1-year follow-up to 6 % at the 6-year follow-up. No data were available on the management strategies, but it is reasonable to assume that there was a time effect, i.e., the longer the time from the primary injury the lower the pain intensity and impact on ADL functions. Very interestingly, the data indicated that only 15 % of the patients with pain/impaired ADL functions belonged to the same category of pain intensity (none, light, moderate, severe) both at the 1- and 6-year follow-up. In other words, of the 30 % (n = 59/174) experiencing moderate to severe intensity pain at the 1-year follow-up, only 16 % (n = 10/59) of these experienced the same intensity of pain at the 6-year follow-up. At the 6-year follow-up, 10 % (n = 18/174) experienced moderate to severe intensity pain. Obviously, the limited number of patients with pain and functional impairment at the 6-year follow-up precludes an affirmative statistical conclusion, but it would seem that a change in phenotype may occur with time. A recent study with a 6-month and 5-year follow-up of 645 GHR-patients, corroborates these findings with a more detailed methodology (Reinpold et al. 2011). In this study, 33 patients reported chronic pain at 6 months but no pain after 5 years. Chronic pain was recorded in 16 patients after both the 6-month and 5-year follow-up. In 36 patients, chronic pain was recorded after 5 years but not after 6 months. These data indicate that more than two-thirds of the PPP-patients develop chronic pain with a late onset! Possible explanations include variability in pain assessment methods, statistical inaccuracies due to low pain ratings (NRS 0–3), changes in analgesic management, development of drug tolerance, hernia recurrence, neuropathic pain, or dehiscence or dislocation of the inguinal mesh. A particularly interesting hypothetical explanation could be related to the reinstatement of latent sensitization (the reader is referred to Sect. 2.1) (Corder et al. 2013). Impairment in sexual activity as a complication to GHR has been well characterized (Aasvang et al. 2006b, 2007; Bischoff et al. 2012). In a nationwide questionnaire study of 805 individuals, pain during sexual activity was reported by 88 patients (10.9 %), of whom 45 (5.6 %) described the pain as mild, 34 (4.2 %) described it as moderate, and 9 (1.1 %) described it as severe (Bischoff et al. 2012). In open-surgery GHR, a prevalence of moderate to severe impairment of sexual activity has been reported in 2.8 % of patients, which is only marginally higher than in laparoscopically assisted repair: 2.4 %. Severe pain during ejaculation (dysejaculation) is seen in 4.0 % after open repair and in 3.1 % after


laparoscopic repair. In studies with different surgical procedures performed at single centers, the prevalence of dysejaculation for open and laparocopical repair have been reported to be 1.6 and 1.0 %, respectively (Aasvang et al. 2010a; Bittner et al. 2010). These rather low prevalences should be contrasted to the large number of GHR procedures performed annually: 2,000 procedures per 1 million adults. It should also be emphasized that this routine procedure generally is performed in otherwise healthy individuals. Unfortunately, there are no detailed studies in GHR on HR-QOL including socioeconomic consequences associated with severe PPP (Kehlet et al. 2013).

4.4 Persistent Pain After Lung Cancer Surgery A number of studies have examined impairment of ADL-functions following LCS, but very seldom comprehensively or as primary objectives (Wildgaard et al. 2009), which indicates a commonality with the studies performed in GHR. Larger studies (70–600 patients), with prevalences of severe pain in the order of 2–8 %, indicate that 40–50 % of the patients experience functional restrictions in everyday life more than 1 year after surgery (Maguire et al. 2006; Perttunen et al. 1999; Tiippana et al. 2003). Other studies demonstrate that 20 % of patients have moderate to severe impairment in their ADL-functions: carrying heavy objects, responding to changes in the weather, walking, lying on the operated side, feeling depressed, and working with the hand of the operated side (Perttunen et al. 1999). In particular, discomfort or restricted motion of range of the shoulder has been reported in 10–20 % of the patients (Dajczman et al. 1991; Khan et al. 2000; Landreneau et al. 1996). In a recent questionnaire-based study of persistent pain after LCS, carried out 2 years after the surgical procedure, the prevalence of perceived sensory changes was independent of the surgical procedure, the less traumatic video-assisted thoracic surgery (VATS) compared to open-surgery thoracotomy, with 75 % experiencing the sensory changes in the rib area (Wildgaard et al. 2011). Activities like carrying heavy bags, performing moderate and light physical activity, vacuum cleaning, lying on the operated side, and elevating arm/using arm above the horizontal level were impaired by pain in more than 60 % of the patients. The prevalence of persistent pain after LCS was similar when comparing type of adjuvant treatment, i.e., radiotherapy or chemotherapy, or, type of surgery. Clinically relevant pain (NRS [ 3) during rest, walking, and when physically active, was present in 39, 51, and 65 % of the lung cancer patients, respectively. Corresponding assessments for severe pain (NRS [ 5) were 14, 17, and 42 %, respectively. A fairly limited number of studies are available on health-related QOL issues in LCS-patients compared to BCS-patients (Poghosyan et al. 2013). Of 19 studies, 11 did not extend the follow-up beyond 12 months, partly attributable to the low


survival rate of lung cancer patients (Walters et al. 2013). The most prevalent principal symptoms affecting HR-QOL were pain, fatigue, dyspnea, and coughing.

5 Pathophysiology 5.1 General Aspects The putative etiologies for PPP are: a continuing inflammatory response; a neuropathic component; a late reinstatement of postsurgical inflammatory pain; or a combination of these. In particular, the neuropathic component has attracted much scientific interest (Kehlet et al. 2006; Borsook et al. 2013), as previously stated, though the prevalence of any of these pain components is currently not known for any surgical procedure. Surgical tissue injury generates immediate activation of nociceptors; physiological nociception.5 It signals presence, location, intensity, and duration of the noxious stimulus and fades rapidly once the surgical stimulus is removed (Kehlet et al. 2006). Inflammatory-mediated nociception is initiated minutes after the tissue trauma, by activation of complex cascade systems: classical inflammatory mediators; cytokines; TRP-channels; and neurotrophins. These responses lead to peripheral sensitization with a reduction in thresholds of nociceptors (primary hyperalgesia), to ‘‘wind-up’’-like phenomena6 and to central sensitization (Woolf 2011), with increased excitability of neurons in the central nervous system, including activation of glial cells (Scholz and Woolf 2007). These changes contribute to exaggerated responses to innocuous sensory input [secondary hyperalgesia, long-term potentiation (LTP)]. Inflammatory hypersensitivity may be present for days to weeks depending on the severity of the tissue injury. Enhanced excitation and impaired inhibition are basic pro-nociceptive mechanisms. Severe tissue injury leads to local and systemic inflammatory responses. Behaviorally these adaptations lead to hyperalgesia and hypersensitivity, and immobilization, limiting the tissue injury and increasing the survival chance of the animal. If these changes continue after the healing process has been completed, they become maladaptive and counterproductive, leading to sustained pain with behavioral consequences (Sandkuhler and Gruber-Schoffnegger 2012). LTP is a complex amplification mechanism in spinal and thalamic neurons that constitutes a painretaining mechanism, i.e., pain ‘‘memory’’. A number of human experimental studies have demonstrated that low-frequency (2–10 Hz) and high-frequency (100 Hz) electrical stimulation (van den Broeke et al. 2010; Biurrun Manresa et al. 2011),

5

Nociception means to pick-up signs of imminent tissue injury. Pain is the conscious perception of nociception. 6 ‘‘Wind-up’’-like activity describes temporal summation, i.e., repeated noxious stimuli will lead to progressively increasing pain.


are associated with several hours of sensitization of the nociceptive pathways that persist after termination of the primary conditioning stimulus. However, extrapolation of data from these experimental studies to PPP is limited by two factors: the time aspect, the LTP-studies only induce fairly short-lasting changes vis-à-vis a chronic pain state; and the pain model—only skin stimulation, a target organ with an inherent low propensity for development of chronic pain, has been used. Impaired function of an endogenous pain inhibition system, the descending conditioned pain modulation system (CPM),7 is an important contributing factor to postsurgical pain sensitivity in humans (Yarnitsky 2010; Yarnitsky et al. 2008). Deficiency in the CPM system has been associated with PPP (Yarnitsky 2010; Yarnitsky et al. 2008) as well as a number of other chronic pain conditions: chronic musculoskeletal pain (Staud et al. 2012), chronic tension-type headache (Pielsticker et al. 2005), chronic pancreatitis (Olesen et al. 2010), fibromyalgia (Price et al. 2002), irritable bowel syndrome (King et al. 2009), temporomandibular disorder (King et al. 2009) and osteoarthritis (Kosek and Ordeberg 2000). However, the causal relationship between the CPM system and chronic pain has yet not been demonstrated: is the impairment in CPM responsible for development of chronic pain or is the impairment in CPM a consequence of chronic pain, the chicken and egg problem revisited?

5.2 Quantitative Sensory Testing Quantitative sensory testing (QST), commonly used in experimental and clinical pain research, investigates the graded psychophysical response to controlled thermal, mechanical, electrical, or chemical stimuli, allowing quantification of clinically relevant perception and pain thresholds (Werner et al. 2013). Persistent pain following surgical procedures represents a unique opportunity to identify pathophysiological contributors, i.e., neuropathic and inflammatory components, and link these to a specific postsurgical pain state (Jensen and Kehlet 2011). Most of the variables studied are associated with the testing of cutaneous sensory function, e.g., neuropathy testing. Assessments of pressure pain, vibratory thresholds, and certain laser stimuli test the function of deeper structures (dermis, fascia, nerves, vessels, musculoskeletal tissues) and may reveal inflammatory origins of pain. 5.2.1 Breast Cancer Surgery An early, pivotal QST-study on PPP, performed in BCS-patients, demonstrated that thresholds to tactile and thermal stimuli were higher on the surgical side as compared to the contralateral side, both in pain and pain-free subjects (Gottrup et al. 2000). Pressure pain thresholds, assessed by pressure algometry, were lower 7

In animals called the diffuse noxious inhibitory control system (DNIC)


on the surgical side in pain patients, while no side-to-side difference was apparent in the pain-free group. No patient in this study had received chemotherapy, which potentially could affect the sensory system, while 6 out of 15 patients had received radiotherapy. The findings indicated first, that sensory hypoesthesia in the skin is a common finding in the surgical field, irrespective of pain status, and second, that hyperesthesia from deeper structures characterize BCS-patients with PPP. Third, signs of an enhanced temporal summation, induced with repetitive 2 Hz pin-prick stimuli, were demonstrated on the surgical side in PPP-patients but not in pain-free subjects. These results have partially been corroborated in other studies (Vilholm et al. 2009; Edwards et al. 2013). Interestingly, a deficiency in the CPM system, i.e. a decrease in endogenous pain inhibition, has recently been reported in PPP patients (Edwards et al. 2013). In a study with assessment of pressure pain thresholds in areas distant from the surgical field (neck, deltoid muscle, hand, and lower leg), significantly lowered thresholds were demonstrated in BCS-patients compared to healthy controls, indicating signs of widespread musculoskeletal sensitization (Fernandez-Lao et al. 2011). A high-powered study with pain (n = 102) and pain-free (n = 98) BCSpatients (Schreiber et al. 2013) confirmed these results, but could not demonstrate changes in thermal thresholds and temporal summation tests outside the surgical field. 5.2.2 Groin Hernia Repair Quantitative sensory findings in GHR-patients (open surgical technique) and BCSpatients are quite similar. The GHR-patients demonstrated increased tactile thresholds, cool and warmth detection thresholds, and heat pain thresholds on the surgical side compared to the nonsurgical side, both in-pain patients and pain-free controls (Mikkelsen et al. 2004; Aasvang et al. 2008, 2010b). Sensory mapping, with a metal roller, demonstrated preferential hypoesthesia in the surgical field in both pain and pain-free groups. However, increased tactile thresholds (Aasvang et al. 2008), decreased tactile pain thresholds (Aasvang et al. 2010b), decreased pressure pain thresholds (Aasvang et al. 2008, 2010b), increased thermal thresholds (Aasvang et al. 2010b), and temporal summation to mechanical stimuli (Aasvang et al. 2010b), assessed on the surgical side, distinguished PPP-patients from pain-free controls. This indicates a hypersensitivity to noxious mechanical stimuli and hyposensitivity to thermal stimuli in the GHR-patient with PPP compared to pain-free GHR controls. Interestingly, pressure hyperalgesia and cool hypoesthesia were observed in the non-surgical side in GHR-patients with PPP, but not in pain-free GHR controls (mirror-image findings, please see below) (Aasvang et al. 2010b). In a study of laparoscopically operated PPP-patients, the findings of a number of pain localizations outside the inguinal region, clearly separated this group from the group with open-surgery GHR (Linderoth et al. 2011). These QST data indicate that inflammatory, mechanical, and neuropathic components are potential contributors to persistent pain in GHR-patients.


5.2.3 Lung Cancer Surgery Thermal and mechanical detection thresholds are increased, reflecting a sensory hypofunction on the surgical side, compared to the nonsurgical side, both in-pain patients and pain-free controls after LCS. This seems to indicate that LCS is the cause of development of neuropathy in the surgical field (Kristensen et al. 2010; Wildgaard et al. 2012a, b). In LCS-patients with persistent pain, more extensive disruption of thermal sensory function (increased thresholds) is seen compared to pain-free LCS controls (Wildgaard et al. 2012a), indicating a predominantly neuropathic origin of pain. These findings are in agreement with a number of other LCS studies (Duale et al. 2011; Guastella et al. 2011; Wildgaard et al. 2013a, b). Recent studies have demonstrated that single QST assessments in LCS-patients with PPP carry an excessively high variability in thermal thresholds, necessitating the use of repeated testing in order to acquire reliable data (Wildgaard et al. 2013b). In a companion study mapping thoracic areas by simple metal rollers, deviations of cool and warmth perception were recorded, using a test–retest technique. Mirror images of the sensory changes on the surgical side were replicated on the nonsurgical side in 12 out of 14 patients (Werner et al. 2013). The exact neural mechanism implicated in this ‘‘crosstalk’’ between the pathologically changed side and the contralateral normal side, is not known, but animal data indicate that it depends on a glial cell inflammatory response with subsequent release of cytokines leading to the activation of central neural pathways (Obata et al. 2010). In conclusion, the QST-profiles following BCS, GHR, and LCS exhibit common denominators for pain patients and pain-free controls: increased tactile and thermal thresholds on the surgical side compared to the nonsurgical side, probably constituting an injury-induced, stereotype imprint upon the nervous system. The QST-profiles in PPP-patients, across the three surgical procedures, also demonstrate similarities: the increases in thermal thresholds seem to be accentuated compared to pain-free individuals. In addition, BCS-patients and GHR-patients with PPP present with increased tactile thresholds, decreased pressure thresholds, and augmented temporal summation in the surgical field, indicating the presence of both inflammatory and neuropathic components with a significant contribution of central sensitization.

6 Predictive Factors 6.1 Surgical Factors A number of surgical factors associated with PPP have been identified, including increased duration of surgery (Peters et al. 2007), low surgical volume (Tasmuth et al. 1999), repeat surgery (Aasvang et al. 2006a), use of more invasive surgical techniques (Aasvang et al. 2010a) and intraoperative nerve lesion (Wildgaard et al. 2009;


Katz and Seltzer 2009). Surgical procedures like VATS, laparoscopic cholecystectomy, or laparoscopic groin hernia surgery are associated with decreased probability of development of PPP, compared with open-surgery procedures. These surgical noninvasive techniques decrease the risk of nerve lesion in BCS, GHR, and LCS, and it is reasonable to assume that this is a major factor for the improved outcome. In addition, the sentinel node technique in BCS, with breast tissue conserving therapies, has dramatically decreased the prevalence of PPP (Gartner et al. 2009). In implant surgery like GHR, use of lightweight mesh and glue fixation has, in laparoscopic GHR, reduced the prevalence of PPP (Bittner et al. 2010). It should however, be emphasized that one of the most consistent predictive factors for PPP is high intensity acute postsurgical pain (Andersen and Kehlet 2011; Kehlet et al. 2012), implicating the necessity for joint efforts by surgeons and anesthesiologists in the prevention and management of acute pain.

6.2 Psychological Factors Psychological factors, i.e., attentional bias to pain, anxiety, catastrophizing behavior, depression, introverted personality, and psychological vulnerability, have all been identified as significant predictors of PPP (Hinrichs-Rocker et al. 2009; Lautenbacher et al. 2011; Theunissen et al. 2012). A recent study compared dependence of specific psychological predictors (anxiety, catastrophizing behavior, and depression) on two different surgical procedures, BCS and total knee arthroplasty (Masselin-Dubois et al. 2013). The breast cancer group was younger and seldom restricted by preoperative pain, while the knee osteoarthritis group was older and suffering from impaired mobility and preoperative pain. From a psychological perspective, these groups are quite different, since breast cancer is obviously a potential life-threatening disease associated with existential thoughts and fears, while knee osteoarthritis is a slower, degenerative disease often received with relative stoicism in the elderly. Multivariate logistic regression analyses indicated that clinically significant PPP at 3 months was predicted independently by age, immediate postsurgical pain intensity, and state anxiety (as opposed to inherent [trait] anxiety). Linear regression models also showed that pain magnification, one of the three dimensions of catastrophizing, independently predicted chronic pain intensity. Interestingly, any procedure-specific dependence of these psychological factors was not demonstrated in this study.

6.3 Socioeconomic Factors It is quite amazing, in our increasingly cost–utility conscious societies, how little attention has been paid to PPP, pain-related functional impairment, social consequences, and influence on societal cost-issues, i.e., sick leave, early retirement,


transfer incomes, and healthcare expenditures (Gilron and Johnson 2010; Kehlet et al. 2013). Swedish data, based on a population of nine million inhabitants, indicate that the annual expenditure for patients with a diagnosis related to chronic pain, in the period of 2004–2009, was estimated at 42 billion USD, corresponding to 10 % of the gross national product (GNP) of Sweden (Gustavsson et al. 2012). Unfortunately, it is not possible from these data to extract detailed expenditure data for PPP-patients, but a reasonable estimate is that 1–5 % of this cost is related to severe PPP.

6.4 Biological Factors 6.4.1 Genetics Pain perception is genetically a very complicated trait, consisting of an aggregate of phenotypes affected by peripheral and central nervous system dynamics, inflammatory dynamics, physical stress dynamics, and distress responsiveness (Smith et al. 2012). Based on animal studies, estimates of heritability of indices of pain sensitivity generally conclude that 30–75 % of the variation in pain responding is explained by genetic factors (Young et al. 2012). Significant discoveries have been made mapping single gene characteristics, characterizing the genetic variation by single nucleotide polymorphisms (SNPs). A number of SNPs are associated with phenotypically increased sensitivity to pain: polymorphisms of the genes OPRM1, CACNAD2, ABCB1, COMT, GCH1, and SCN9A8 (Kehlet et al. 2012; Rhodin et al. 2013). A statistically superior method, called genomewide association (GWA) studies, focuses on associations between multiple SNPs and phenotype, e.g., pain sensitivity. The GWA studies more accurately delineate the often complex interactions between a large number of SNPs. However, GWA studies may require tissue sampling from 1,000 up to 100,000 individuals (Smith et al. 2012).

6.4.2 Quantitative Sensory Testing Preoperatively assessed QST-variables, as potential predictors of acute and chronic postsurgical pain, have been used in a number of studies (Katz and Seltzer 2009; Ip et al. 2009; Werner et al. 2010; Werner and Kehlet 2010; Abrishami et al. 2011). However, only two predictive studies are presently available on the three surgical procedures presented in this chapter (Aasvang et al. 2010a; Yarnitsky et al. 2008).

8 OPRM1: l-opioid receptor; CACNA2D2: voltage-dependent calcium channel subunit a2d-2; ABCB1: ATP-binding cassette B1 transporter enzyme; COMT: catechol-O-methyl transferase; GCH1: GTP cyclohydrolase 1; SCN9A: encoding the expression of Nav1.7 ion channel.


In a high-powered study, patients scheduled for GHR, by open (n = 244) or laparoscopic (n = 198) surgery, were examined preoperatively with functional assessments by a groin hernia specific pain-related activity scale (AAS-score), pain ratings, psychometrics, QST variables, and pain responses to tonic heat stimuli (Aasvang et al. 2010a). The 1- and 6-month’s follow-up after GHR, demonstrated four significant risk factors for development of PPP: preoperative AAS-score, preoperative pain to tonic heat stimulation, 1-month postsurgical pain intensity, and sensory dysfunction in the groin at the 6-month follow-up. In a predictive, multiple regression model containing preoperative variables and surgical technique, three risk factors for development of PPP were identified: a preoperative AAS-score indicating a high degree of preoperative physical impairment, an increased preoperative pain response to heat stimulation, and surgery performed by an open procedure. An interesting, predictive QST study in 62 patients scheduled for thoracotomy (number of LCS-patients not stated) examined the preoperative CPM-efficiency, i.e., the efficacy of the endogenous pain-inhibiting system (Yarnitsky et al. 2008). The conditioning stimulus was immersion of the hand in 46.5 8C water for one min. The test stimuli were 30-second contact heat impulses delivered at the contralateral forearm and maintained at a temperature level, initially corresponding to a pain perception of 60 on a numerical rating scale of 0–100. Patients with an efficient CPM system preoperatively experienced a reduction in pain perception of the test stimuli, during and immediately after the conditioning stimulus. The patients were followed in mean (SD) for 7 months (4 months) after the surgical procedure. The preoperatively assessed CPM-efficiency significantly predicted a lowered risk of development of PPP: odds ratio of 0.52 (0.33–0.77; 95 % CI). Thus an efficient CPM system seems to protect against PPP. Further procedure-specific studies are, however, needed to corroborate these findings (Lewis et al. 2012), but a predictive potential for PPP by assessment of efficiency of the descending inhibitory system has been demonstrated (Granovsky 2013).

6.4.3 Neuroimaging A number of neuroimaging studies related to acute and chronic postsurgical pain have been published during recent years (Pogatzki-Zahn et al. 2010; Gwilym et al. 2010; Howard et al. 2011). Neuroimaging techniques have revealed structural and functional changes in the brain related to the chronic pain state (Borsook et al. 2013). These changes are localized to regions primarily involved in pain processing (thalamus, posterior insula, and primary somatosensory cortex) and pain modulation (anterior cingulate cortex), but also regions involved in emotional processing of pain (anterior cingulate cortex, insula, periaqueductal gray substance), premotor activity (supplemental motor areas, cerebellum), and cognitive processing (anterior cingulate cortex, prefrontal cortex) (Borsook et al. 2013). Interestingly, decreases in brain gray matter density have been demonstrated in chronic pain patients, e.g., chronic back pain, complex regional pain syndrome,


and knee osteoarthritis (Baliki et al. 2011). These morphometric changes have preferentially been demonstrated in the anterior cingulate cortex, insular cortex, prefrontal cortex, and amygdale, including the brainstem (Rodriguez-Raecke et al. 2009; Emerson et al. 2014). The exact mechanisms underlying these structural changes remain obscure and cell atrophy (affecting neurons or glia cells), cell death or synaptic loss as well as simple decreases in cell size, interstitial fluid density, or blood volume has been suggested as possible explanations (Draganski and May 2008; Rodriguez-Raecke et al. 2009). However, the decrease in brain gray matter density, in chronic pain patients seems to be a reversible process; in patients with osteoarthritis pain, successful hip replacement surgery, assessed by behavioral indices, is associated with an increase in the brain gray matter density in the involved cortical areas (Rodriguez-Raecke et al. 2009; Gwilym et al. 2010). Similar structural brain changes have also been demonstrated in patients with chronic low back pain undergoing spine surgery, facet joint injections (Seminowicz et al. 2011) or topical analgesic treatment (Baliki et al. 2008). Interestingly, in the former study, patients after treatment had an increase in cortical gray density matter in the left dorsolateral prefrontal cortex, an increase that correlated with reduction in pain and physical disability. Even more interesting was that increases in cortical gray matter density in right anterior insula and in the primary motor cortex were specifically associated with reduced pain and with reduced physical disability, respectively (Seminowicz et al. 2011). These findings illustrate very aptly the synergistic interaction between pain and physical impairment: reduction in either pain or in physical impairment may lead to improvement of the other, while increase in either pain or physical impairment may lead to deterioration of the other. A number of animal and human studies have shown cortical structural effects of exercise (Draganski and May 2008; Scheef et al. 2012), which is of critical importance for evaluation of management strategies.

7 Future Research Strategies The literature base of this overview clearly indicates that in studies of PPP, a plethora of research methods, yielding a large number of different outcomes, has been used. Consensus on optimal study designs and psycho-physiological research methods would facilitate interpretation of data leading to improvements in diagnosis, management, and preventive measures in postsurgical pain. The recommendations from IMMPACT (Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials) (Dworkin et al. 2008, 2010) and ACTION (Analgesic Clinical Trial Innovations, Opportunities, and Network initiative) (Rappaport et al. 2010; Dworkin et al. 2011) have the potential to serve as useful platforms. Another problem is our lack of knowledge concerning the pathophysiological mechanisms behind PPP. The principal question here is: is the pain neuropathic, inflammatory, or of mechanical origin? The accepted criteria for neuropathic pain are (Treede et al. 2008):


1 Pain with a distinct neuroanatomically plausible distribution. 2 A history suggestive of a relevant lesion or disease affecting the peripheral or central somatosensory system.9 3 Demonstration of the distinct neuroanatomically plausible distribution by at least one confirmatory test.10 4 Demonstration of the relevant lesion or disease by at least one confirmatory test.11 According to Sect. 5.2, it seems that the criteria for neuropathic pain in PPP-patients, across the three surgical procedures considered in this chapter, are fulfilled, with a grading certainty of the diagnosis of definite neuropathic pain or at least probable neuropathic pain (please see the footnotes). However, there is a didactic problem: pain-free, postsurgical controls, fulfill the same criteria as the PPP-patients, except for the existence of pain, meaning either, that the expression of pain in postsurgical neuropathy is highly variable (Kalliomaki et al. 2011), or that inflammatory or mechanical components, disguised as neuropathic ‘‘pain,’’ are contributing to the pain state. The QST data seem to indicate that inflammatory or mechanical components play a substantial part in the PPP state following BCS and GHS. Future strategies in PPP should include procedure-specific research targeted at elucidating basic mechanisms underlying the pain state and, if possible, assess the relative contribution of neuropathic, inflammatory, and mechanical components. Remember the patient with a lump in the groin introduced at the beginning of the chapter, who had an open GHR performed? The indications for performing GHR in reducible hernias are primarily preventive, as mentioned, to forestall complications and to relieve discomfort and pain (Metzger et al. 2001), and secondarily, to cosmetically improve the physical defect. Could the patient’s postsurgical suffering have been foreseen? As described in Sect. 6.4.2, increased preoperative AAS-scores, increased preoperative pain to heat stimulation, and a planned open surgical procedure, increase the risk significantly for development of PPP (Aasvang et al. 2010a). If the patient’s preoperative examination had revealed moderately impaired physical function prior to surgery and a pain rating of the heat stimulus as severe (NRS = 9), a preoperative risk calculation would have estimated a risk of development of PPP following open surgery of 42 % and laparoscopic surgery of 22 %. If laparoscopic surgery had been performed the risk of PPP would have been decreased by 50 % (Aasvang et al. 2010a)!

9

The suspected lesion or disease is reported to be associated with pain, including a temporal relationship typical for the condition. 10 As part of the neurologic examination, these tests confirm the presence of negative or positive neurologic signs concordant with the distribution of pain. Clinical sensory examination may be supplemented by laboratory and objective tests to uncover subclinical abnormalities. 11 As part of the neurologic examination, these tests confirm the diagnosis of the suspected lesion or disease. These confirmatory tests depend on which lesion or disease is causing neuropathic pain.


Since the preoperative examinations revealed the patient to be in a high-risk group, amendments to the surgical procedure, such as use of lightweight mesh and fixation with glue, could, in addition to the laparoscopical procedure, have reduced the risk of development of PPP. Future procedure-specific research should focus on procuring simple reliable predictive indices of acute and PPP. Neuroimaging techniques should be used in experimental predictive studies. A recent morphometric MRI-study in human volunteers demonstrated a strong correlation between greater thermal and pain sensitivity and cortical thickening of the primary somatosensory cortex (Erpelding et al. 2012). It will be of interest to determine if patients with increased gray matter volume of the primary somatosensory, the posterior mid-cingulate, and the orbito-frontal cortex are at greater risk of developing PPP than controls.

8 Conclusion With an extrapolated total global, annual volume of 235 million surgeries (Weiser et al. 2008) and estimating that 2–10 % of the patients are impaired by severe persistent postsurgical pan, major causes of human hardship and strain on healthcare resources are recognized. Surgery is pivotal in management of breast cancer, groin hernia repair, and lung cancer, and the benefits to the patients are unquestionable; but the quest of identifying improved surgical and anesthesiological techniques to prevent or mitigate severe pain and functional impairment in patients after surgery, continues.

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Neural blockade for persistent pain after breast cancer surgery.

Preoperative Breast Pain Predicts Persistent Breast Pain and Disability After Breast Cancer Surgery.

Reoperation for persistent pain after groin hernia surgery: a population-based study.

Persistent pain following groin hernia repair: what is the best practice in pain management?

Can acute pain treatment reduce postsurgical comorbidity after breast cancer surgery? A literature review.

Associations between cytokine gene variations and severe persistent breast pain in women following breast cancer surgery.

Effect of Preoperative Inflammatory Status and Comorbidities on Pain Resolution and Persistent Postsurgical Pain after Inguinal Hernia Repair.

shoulder pain following breast cancer surgery.

Predicting, preventing and managing persistent pain after breast cancer surgery: the importance of psychosocial factors.

Predictive factors for the development of persistent pain after breast cancer surgery.

Innate immune function after breast, lung, and colorectal cancer surgery.

Surgery for liver metastases from breast cancer.

[Surgery of breast cancer].

[Lung cancer surgery and cirrhosis].

Pain at 12 months after surgery for breast cancer.

Postsurgical chemotherapy vs. surgery alone for resectable gastric cancer.

Persistent Pain after Dental Surgery.

Variations in potassium channel genes are associated with distinct trajectories of persistent breast pain after breast cancer surgery.

Emergency groin hernia repair: implications in elderly.

Robotic surgery for lung cancer.

Surgery for early breast cancer.

Selective surgery for breast cancer.

Lipofilling in breast cancer surgery.

Surgery for early breast cancer.